tbuckley/cabot-search huggingface dataset:
SURG-28. ADULT MIDLINE GLIOMAS TREATED WITH LASER INTERSTITIAL THERMAL THERAPY (LITT): OUR COMPARATIVE EXPERIENCE WITH NEEDLE BIOPSY
Authors: Martin Merenzon, Francisco Marcó del Pont, Alexis Morell, Dominique Higgins, Nitesh Patel, Michael Kader, Adam Levy, Tiffany Eatz, Daniel Eichberg, Ashish Shah, Michael Silva, Evan Luther, Victor Lu, Ricardo Komotar, Michael Ivan
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Adult midline gliomas are rare entities, with a scarcity of available clinical data. These patients have variable courses, with limited evidence to predict outcomes. Emerging evidence suggests that biomolecular profiles may play a significant role in outcomes, so tissue diagnosis is a key component of management. However, the role of cytoreductive therapy, such as Laser Interstitial Thermal Therapy (LITT) remains unknown. To date, only a few studies have described the use of MRI-guided LITT for managing midline gliomas. OBJECTIVE To present a retrospective analysis of a single-center two-surgeon experience treating adult midline gliomas with either biopsy/LITT or biopsy alone. METHODS Patients with midline intraxial tumors surgically treated at our tertiary care referral center were identified using our established database. Twenty-one patients managed either with biopsy/LITT or needle biopsy from 2015 to 2021 were included. Demographics and clinical records including, among others, length of hospital stay, preoperative lesion size, ablation volume, perioperative complications, adjuvant treatment, and stratified overall survival (OS) were collected. RESULTS The two cohorts were composed of 7 patients who underwent LITT, and 14 biopsies. The mean age was 60.95y (25-82). The average tumor volumes were 16.99 cm3 and 15.41 cm3 for LITT and biopsy, respectively. No post-surgical complications were found in the LITT group, one patient had a postsurgical hemorrhage after biopsy. The mean OS was 20.28 ± 9.63 months in the LITT group, which was greater but not statistically significant than in the biopsy group (11.05 ± 4.45 months) (p = 0.605). CONCLUSION Our results show that LITT is as safe as needle biopsy for the treatment of adult midline gliomas, and may offer a survival benefit given its cytoreductive properties.
DNAR-03. TARGETING POLY (ADP-RIBOSE) SIGNALING TO INDUCE LETHAL DNA DAMAGE IN IDH MUTANT GLIOMA
Authors: Yosuke Kitagawa, Hiroaki Wakimoto, Lisa Melamed, Ali Nasser, Julie Miller, Daniel Cahill
Journal: Neuro-Oncology (2022)

Abstract Isocitrate dehydrogenase (IDH) 1 or 2 mutant gliomas have unique metabolic characteristics and DNA damage response. Radiotherapy and chemotherapy has been proven to be an effective treatment for IDH mutant gliomas. A key mediator of DNA damage response, Poly(ADP-ribose) (PAR) is regulated by opposing enzymes, poly(ADP-ribose) polymerases (PARPs) that synthesizes PAR through enzymatic polymerization of nicotinamide adenine dinucleotide (NAD), and poly(ADP-ribose) glycohydrolase (PARG) that breaks down and recycles PAR. We recently demonstrated that combining PARG inhibitor (PARGi) and Temozolomide (TMZ) in IDH mutant cells drove an imbalanced sequestration of NAD into PAR, resulting in metabolic lethality through NAD depletion. Here, we sought to characterize the effect of combining PARGi and radiation. Isogenic pairs of IDH1-mutant glioma cells, alongside multiple IDH mutant patient-derived glioma cells, were treated with TMZ, radiation, PARPi, PARGi, and combination thereof. In contrast to PARPi which can have a “trapping” effect, PARGi monotherapy displayed no significant difference between IDH mutant and wild-type isogenic cells. However, we found a substantial augmentation of radiation cytoxicity when combined with PARGi, that was genotype-specific in IDH mutant glioma models, mirroring that seen with PARPi and radiation (Wang et al, Science Advances 2020). Unlike TMZ+PARGi, NAD was not depleted with PARGi and radiation. Conversely, the cytotoxic effect was partially reversed with either PARPi or IDH inhibitor, indicative of a key contribution of PAR mediated DNA damage signaling in the IDH mutant context. Therefore, these results support a model of converging vulnerabilities in IDH mutant cells, with PAR-mediated DNA repair mechanisms independent from NAD metabolism.In summary, this study demonstrates that the combination of PARGi and radiation regulates DNA repair pathways with cytoxicity specific to IDH mutant gliomas. Targeting PAR can potentially be a promising treatment for clinical translation in IDH mutant gliomas, minimizing the radiation effect to surrounding normal cells.
RADT-09. PREOPERATIVE STEREOTACTIC RADIOSURGERY FOR LARGE CEREBRAL METASTASES – A PROSPECTIVE CLINICAL TRIAL SHOWING EFFICACY AND DECREASED TIME TO RESUMPTION OF IMMUNOTHERAPY
Authors: Arka Mallela, Uzoma Iheagwara, David Fogg, Austin Walker Anthony, Xiaoran Zhang, Zachary Gersey, Hussam Abou-Al-Shaar, Emily Xu, Pascal Zinn, Steve Burton, Annette Quinn, David Clump, Zaid Siddiqui, Nduka Amankulor
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Preoperative stereotactic radiosurgery (SRS) is an emerging therapeutic strategy for treatment of brain metastasis requiring surgical resection. Prior reports have been highly-controlled, excluding very large brain metastases. Here, we report a prospectively-collected preoperative series reflective of a real-world neurosurgical patient cohort, with a particular focus on resumption of immunotherapy. METHODS Our series included Nf27 prospective preoperative compared to concurrently collected Nf37 postoperative patients. Demographic, SRS volumes/dose, pre/postoperative immunotherapy, and clinical outcomes were collected. Subsequent univariate comparisons between groups were performed. RESULTS Pre/postoperative tumor volumes (19.1 [range: 2.4-65.1] vs. 12.5 [3.6-80.3]cc, p=0.20); local tumor control at 1 year (77.6% vs. 71.4%, p=0.616); overall survival (1.0 [0.8-2.2] vs. 1.3 [0.7-NR] years, p=0.8) were comparable between groups. Rates of LMD (3.7% vs. 8.0%, p=0.39) and subsequent WBRT (8.0% vs. 16.2%, p=0.46) were not statistically different. OR time (168 vs. 173 min, p=0.64), estimated blood loss (133 vs. 180 mL, p=0.31), and wound infections (1 vs. 1, p=1.00) were not significantly different.An ostensible advantage to preoperative SRS is that steroids may be weaned more quickly to allow resumption of immunotherapy. Median steroid taper length was significantly shorter (8 vs. 21.5 days, p=0.007), and median daily Dexamethasone dose at 1 week post-op was significantly lower in the preoperative group (1 vs. 7mg d, p=0.007). All preoperative patients eligible for resumption of immunotherapy (Nf5) resumed treatment within 6 weeks. Conversely, only 2/6 in postoperative patients resumed treatment within 6 weeks, (p=0.07), while 4 failed to resume immunotherapy altogether. In patients initiating immunotherapy after OR/SRS, time to initiation was non-significantly lower in the preoperative group (52[38-84] vs.163[108-208] days, p=0.06). CONCLUSIONS Preoperative SRS is safe and provides comparable local tumor control rate even in large tumors ( &amp;gt;20cc). In patients requiring resumption of immunotherapy, preoperative SRS may provide a faster pathway towards resumption of systemic therapy.
INNV-08. CASE REPORT OF AN OLDER GLIOBLASTOMA PATIENT SURVIVING MORE THAN 12 YEARS AFTER TREATMENT WITH CILENGITIDE IN ADDITION TO STANDARD THERAPY
Authors: Huda Alalami, Jethro Hu, Xuemo Fan, Serguei Bannykh
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma is the most common malignant brain tumor. Less than 1% of patients survive longer than 10 years. Integrins are implicated in tumorigenesis due to their role in cell adhesion and intercellular communication. Cilengitide, a selective αvβ3, and αvβ5 integrin inhibitor, was studied for patients with glioblastoma. RESULTS A 77-year-old woman was found to have a left temporoparietal MGMT methylated glioblastoma after presenting with visual field deficits in 2009. She underwent near gross total resection of the tumor. The tumor had retained expression of PTEN and MAPK. No mutations in IDH or ATRX were detected. Genetic testing revealed mutations in TERT promoter, TP53, SYNE1, NF1, PTEN, FBXW7, POLD1, ERG, and PRKDC. She was enrolled in the CENTRIC trial, a phase III clinical trial studying the addition of cilengitide to standard therapy for patients with newly diagnosed glioblastoma with methylated MGMT promoter. In 2013, the initial results of the study failed to meet the endpoint of prolonged overall survival and progression-free survival, therefore the study was halted. The patient received cilengitide through compassionate use until 2016. Surveillance brain MRI obtained every three shows no radiographic evidence of recurrence. CONCLUSION Although it is known that methylated-MGMT promoter is one of the few positive prognostic factors in GBM, overall survival remains poor in older patients. This case highlights a rare clinical response to treatment in an older female who has survived more than 12 years without disease recurrence after receiving cilengitide in addition to standard therapy. Her outcome may have been influenced by the expression of PTEN and the methylation of MGMT, which are associated with improved outcomes. Although the development of cilengitide was halted for lack of efficacy, the existence of individual responders such as this patient suggests that further study of integrin inhibition for glioblastoma patients may be worth pursuing.
CNSC-26. NETWORK SIGNATURES OF SURVIVAL IN BRAIN TUMOUR GENETICS
Authors: James Ruffle, Samia Mohinta, Guilherme Pombo, Robert Gray, Valeriya Kopanitsa, Faith Lee, Sebastian Brandner, Harpreet Hyare, Parashkev Nachev
Journal: Neuro-Oncology (2022)

Abstract Tumor heterogeneity is increasingly recognized as a major obstacle to therapeutic innovation across neuro-oncology. Gliomas typically exhibit a spectrum of possible genetic mutations, reflecting multiple, potentially complex interactions across distinct molecular pathways. Predicting disease evolution and prescribing individually optimal treatment plausibly requires statistical models complex enough to capture the intricate genetic structure underpinning oncogenesis. Here we formalize this task as the discovery of distinct patterns of connectivity within network representations of the interactions between genetic loci. Evaluating multi-institutional clinical, genetic, and outcome data from 7847 consecutive patients over a 14-year period, we employ Bayesian stochastic block modelling to reveal a hierarchical network structure of tumor genetic interactions spanning (molecularly confirmed) IDH-wildtype glioblastoma, IDH-mutant oligodendroglioma and astrocytoma. We show that this structure not only identifies the patients’ diagnosis, but predicts individual survival with greater fidelity (Cox’s proportional hazard cross-validated (CPH-CV) concordance = 0.78; Bayesian 12, 24 and 36-month survival models = R2 0.31, 0.40 and 0.46, respectively) than the latest WHO tumor classification (CPH-CV concordance = 0.77; Bayesian 12, 24 and 36-month survival models = R2 0.26, 0.36 and 0.39, respectively) or linear models of genetic features (CPH-CV concordance = 0.76; Bayesian 12, 24 and 36-month survival models = R2 0.26, 0.35 and 0.37, respectively). For example, a diagnosis of IDH-wildtype glioblastoma yielded median survivals varying from 289 days in patients with the signature of marked EGFR amplification, MGMT methylation, and histone mutations, to 425 days in those with the signature of TERT mutations, histone and EGFR wild-types, and variable MGMT methylation. These findings suggest network-based analysis can reveal distinct signatures of survival with better prognostic fidelity than current gold standard diagnostic categories.
TMET-14. TUMOR-ASSOCIATED MYELOID CELL-DERIVED CREATINE PROMOTES GLIOBLASTOMA GROWTH IN HYPOXIC NICHES AND PSEUDOPALISADING TUMOR REGIONS
Authors: Andrew Zolp, Aida Rashidi, Tzu-Yi Chia, Crismita Dmello, Victor Arrieta, Junfei Zhao, Brandyn Castro, Steven Markwell, Deiter Henrik Heiland, Daniel Brat, Navdeep Chandel, Maciej Lesniak, Catalina Lee-Chang, Jason Miska
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) consists of a unique tumor microenvironment (TME) dominated by infiltrating tumor-associated myeloid cells (TAMCs). TAMCs are central to tumor growth and understanding how they support tumor progression is critical to identifying new therapeutic modalities. Examination of the metabolic and genetic phenotypes of TAMCs revealed that the de-novo creatine phenotype is central to their identity. Immunohistochemistry and multiplex fluorescence in GBM patient-derived tissue showed TAMC infiltration localizing to hypoxic pseudopalisading regions. Furthermore, single-cell RNAseq analysis of human and mouse models of GBM identified that the transporter of creatine, Slc6a8, is located on tumor cells within these regions. Spatial transcriptomics confirmed this transporter-synthesis gene compartmentalization is specific to hypoxic pseudopalisading regions, and further elucidated a radial glial cell gene signature for tumor cells expressing Slc6a8. Murine models recapitulated the TAMC de-novo creatine metabolic phenotype both ex-vivo and in-vitro. Metabolomics showed that TAMC-derived creatine can transfer to tumor cells in-vitro and is enhanced under hypoxic conditions. β-guanidinopropionic acid (β-GPA) is a creatine analog proposed to block Slc6a8 function and effectively blocked TAMC-derived creatine transfer to tumor cells in-vitro. Furthermore, β-GPA inhibited both the viability and size of spheres for tumor cells grown in stem-cell conditions. Lastly, inhibition of creatine transport using clinically relevant inhibitors enhanced survival following tumor implantation in murine models. This work highlights the key role of creatine in the pseudopalisading and hypoxic niche in GBM, offering evidence for a potential benefit in targeting this axis for GBM therapy regimens.
CTNI-48. TRIAL UPDATE -RESULTS OF A PHASE I WINDOW OF OPPORTUNITY TRIAL EVALUATING A FIRST-IN-CLASS CD29 INHIBITOR, OS2966, IN RECURRENT HIGH-GRADE GLIOMA
Authors: James Liu, Anne-Marie Carbonell, Chibueze Nwagwu, Amanda Immidisetti, Michael Vogelbaum
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND OS2966 is a first-in-class, humanized, and deimmunized anti-CD29 (β1integrin) monoclonal antibody. CD29 is a mechanosignaling receptor prominently upregulated in glioblastoma. Preclinical studies in mice and non-human primates have demonstrated safety and encouraging efficacy. A phase I clinical trial was therefore initiated to evaluate the safety and feasibility of delivering OS2966 directly to the site of disease via convection-enhanced delivery (CED) in recurrent high-grade glioma patients. METHODS This study employs a 2-part design: In part 1, patients undergo stereotactic tumor biopsy followed by placement of a CED catheter(s) for delivery of OS2966 to the bulk contrast-enhancing tumor. Subsequently, in part 2, patients undergo a clinically-indicated tumor resection followed by placement of CED catheter(s) and delivery of OS2966 to the surrounding tumor-infiltrated brain. Co-convection of gadolinium enables real-time monitoring of therapeutic delivery. A concentration-based accelerated titration design is utilized for dose escalation. Given availability of pre and post-infusion samples, pharmacodynamic data will be analyzed to explore mechanism of action of OS2966. RESULTS Four patients have completed treatment in both study parts. No dose-limiting toxicity or adverse events related to treatment with OS2966 or CED catheter placement have been reported at the first 3 dose levels (ie, doses up to 0.6 mg/mL). For the four patients treated an average of 4.2 mL and 3.2 mL were infused in study parts 1 and 2 respectively. The Vd/Vi ratio ranged from 0.6 to 1.6 in part 1, and from 2.0 to 4.3 in Study Part 2. Analysis of tissue samples collected during the trial has demonstrated decreased VEGF expression post-treatment, with preinfusion samples showing &amp;gt; 50% VEGF expression and post-infusion samples showing 10% expression. Additional pharmacodynamic analysis via tissue-level biomarkers is ongoing and will be presented. CONCLUSION Initial data demonstrate the safety and feasibility of direct intracranial delivery of OS2966.
CNSC-01. THE GENE LANDSCAPE OF LUNG ADENOCARCINOMA PATIENTS WITH PROGRESSIVE DISEASE OF LEPTOMENINGE
Authors: Hainan Yang, Lei Wen, Caicun Zhou
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) provide a better prognosis in EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, the outcome of leptomeningeal metastasis (LM) remains poor. In addition, due to limited access to intracranial tumour tissue, gene alterations associated with leptomeningeal metastasis from lung adenocarcinoma (LM-LUAD) are unclear. METHODS Forty-five patients with LM-LUAD from May 2019 to June 2021 in Guangdong Sanjiu Brain Hospital were enrolled in this study. Seventy-five percent (34/45) of patients with LM harbored EGFR mutations, and patients with progressive disease (PD) of LM had 3rd-generation EGFR-TKI therapy and were defined as Cohort 1; those without 3rd-generation EGFR-TKI therapy were defined as Cohort 2. Next-generation targeted panel sequencing (NGS) was performed in each cerebrospinal fluid (CSF) sample of the two cohorts, and 9/45 LM-LUAD patients had matched plasma (PLA). RESULTS The common gene alterations discovered in the CSF of LM-LUAD were EGFR mutation (34/45, 75%), TP53 (25/45, 56%), CDKN2A (9/45, 20%), ALK (7/45, 16%), CTNNB1 (6/45, 13%), MET (5/45, 11%), APC (4/45, 9%), FGF4 (4/45, 9%), FGF3 (4/45, 9%), ERBB2 (4/45, 9%), and PIK3CG (4/45, 9%). Cooccurring mutations of TP53 and EGFR were found in 49% (22/45) of patients and correlated with poor prognosis. CDKN2A was identified in 20% (9/45) of patients and presented slightly shorter overall survival (OS) than those without (7.1 versus 8.8 months, p=0.2). Cohort 1 had more genes associated with poor prognosis, consisting of CDK4, CDKN2A, PIK3CG, or PIK3CA, and YES1 and MET were more likely to be detected in cohort 2. The alteration of EGFR was comparable between CSF and matched PLA. Incidences of gene alterations such as CDK4, CDKN2A, MET, SOX2, JAK2, BRAF, and PIK3CG were more likely to be identified in CSF. All mutant allele frequencies (MAF) were much higher in CSF than in matched PLA.
STEM-22. EFFECT OF A SRC INHIBITORY PEPTIDE BASED ON CONNEXIN43 ON NEURAL STEM CELLS WITH GLIOMA-DRIVER MUTATIONS
Authors: Andrea Álvarez-Vázquez, Laura San-Segundo, Pilar Cerveró-García, Raquel Flores-Hernández, Claudia Ollauri-Ibáñez, Berta Segura-Collar, Pilar Sánchez-Gómez, Steven M Pollard, Arantxa Tabernero
Journal: Neuro-Oncology (2022)

Abstract Glioblastomas are one of the most malignant tumors. Glioma Stem Cells (GSCs) are a subpopulation of cells resistant to standard treatments, responsible for tumor recurrence. Strong evidence supports that Neural Stem Cells (NSCs) from the subventricular zone (SVZ) are the origin of GSCs. This transition frequently concurs with epidermal growth factor receptor (EGFR) overexpression or mutations, such as EGFRvIII. Our group designed a cell penetrating peptide based on connexin43 (TAT-Cx43266-283) that inhibits the oncoprotein c-Src and therefore targets GSCs, increasing survival in glioma-bearing mice. Because c-Src and EGFR signaling are closely related, we explored the effect of TAT-Cx43266-283 in the transition of NSCs to GSCs. We compared the effect of TAT-Cx43266-283, control peptides, temozolomide and erlotinib, a common EGFR inhibitor, in SVZ NSCs (Control-NSCs) and murine NSC and patient-derived GSCs with key glioma-driver mutations in Nf1, PTEN and EGFR. EGFR signaling pathway was analyzed by Western blot. Furthermore, we are analyzing the effect of TAT-Cx43266-283 in a mouse model where tumors originate from SVZ NSCs with glioma-driver mutations. Our results showed a strong effect of TAT-Cx43266-283 in cell viability of NSCs and patient-derived GSCs with EGFR amplification or active EGFRvIII, without significant effects in Control-NSCs. Importantly, we found a lower effect of temozolomide, erlotinib, and other control peptides in these cells. Western blot analyses suggest that TAT-Cx43266-283 decreases EGFR, EGFRvIII and c-Src activity. Preliminary in vivo results suggest that TAT-Cx43266-283 decreases tumor size and enhances survival in mice bearing gliomas initiated by altered NSCs. So far, our results show that TAT-Cx43266-283 impairs EGFR signaling pathway with the subsequent reduction in the proliferation and survival of NSCs or GSCs with EGFR alterations. These results stress the relevance of TAT-Cx43266-283 as a future therapy against glioblastoma, alone or in combination with other treatments.
PATH-27. INTRAOPERATIVE ASSESSMENT OF IDH MUTATION AS A SURROGATE FOR TUMOR INFILTRATION VIA DESORPTION ELECTROSPRAY MASS SPECTROMETRY IN GLIOMAS
Authors: Hannah Brown, Diogo Moniz-Garcia, Rong Chen, Mark Jentoft, Erik Middlebrooks, Kaisorn Chaichana, Alfredo Quiñones-Hinojosa, Robert Cooks
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Despite advances in cancer biology, surgery and its extent of resection remains the most important prognostic modulator in gliomas, with the distinction between infiltrated and non-infiltrated tissues being an issue at the penumbra. Isocitrate dehydrogenase (IDH) mutation is unique to IDH-mutant glioma cells and can be used as a potential surrogate for tumor infiltration. Here we evaluate desorption electrospray ionization-mass spectrometry (DESI-MS) as a near real-time method for detecting infiltration at the margin of IDH-mutant gliomas. METHODS We conducted a prospective study in which DESI-MS analysis was performed on freshly obtained tissue biopsies to detect the presence of 2-Hydroxyglutarate (2HG), with subsequent review of each sample by a board-certified neuropathologist. RESULTS A total of 247 biopsies from a 49-patient study were previously collected and analyzed at Indiana University. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%, respectively. Subsequent improvement of the method, including the measurement of 2HG relative to an internal control (Glutamate, Glu), allowed for detection of IDH-mutant infiltration at surgical margins. We have collected 183 biopsies (116 core and 67 margin) from 23 patients. Preliminary results of IDH mutation assessments of core biopsies indicate 93% sensitivity, 100% specificity, and 98% accuracy and margin biopsies indicate 88% sensitivity, 100% specificity, and 94% accuracy. Tumor infiltration at the margin of the surgical resection by detection of IDH-mut infiltration was detected in 88% of margin biopsies from IDH mutant tumors (30 of 34 biopsies). CONCLUSION We present a novel method to allow intraoperative evaluation of IDH mutation presence in glioma margin biopsies. Our method and its ongoing validation identified tumor infiltration beyond surgical margins and serves as a foundation for molecularly guided surgery in IDH-mut gliomas via DESI-MS.